Hepato-biliary radiopharmaceutical comprising 2-mercaptoisobutyric acid chelating reduced technetium-99m

ABSTRACT

A radiopharmaceutical comprising 2-mercaptoisobutyric acid chelating reduced technetium-99m for scintigraphically imaging the liver and biliary tract morphology and function and to a method for instantly making the radiopharmaceutical.

United States Patent Winchell et al.

[ Dec. 23, 1975 HEPATO-BILIARY RADIOPHARMACEUTICAL COMPRISINGZ-MERCAPTOISOBUTYRIC ACID CHELATING REDUCED TECHNETIUM-99M Inventors:Harry S. Winchell, Lafayette;

Archie S. Khentigan, San Francisco; Hong Lin, Berkeley, all of Calif.

Assignee: Medi-Physics, Inc Emeryville,

Calif.

Filed: Oct. 18, 1973 Appl. No.: 407,409

US. Cl 424/ 1; 250/303; 260/429 R; 260/429.7

Int. Cl. A6lk 27/04; C07f 7/22; GOlt 1/00 Field of Search 424/ 1;260/429.7, 429 J, 260/429 K, 429 R; 250/303, 363

[56] References Cited UNIT ED STATES PATENTS 3,725,295 4/1973 Eckelmanet al. 252/301.1 R 3,749,913 7/1973 Halpern et al 424/1 X 3,824,3997/1974 Bjork et al. 250/303 X Primary Examiner-Benjamin R. PadgettAssistant Examiner-C. Nucker Attorney, Agent, of FirmSamuel L. Welt; JonS. Saxe; R. Hain Swope [57] ABSTRACT A radiophannaeeutical comprising 2-mercaptoisobutyric acid chelating reduced technetium-99m forscintigraphically imaging the liver and biliary tract morphology andfunction and to a method for instantly making the radiopharmaceutical.

7 Claims, N0 Drawings HEPATolL ARy RADIOPIIARIl/IACEUTICAL COMPRISINGZ-MERACAPTOISOBUTIYRIC, ACID CHELATING REDUCED TECHNETIUM-99M BACKGROUNDOF THE INVENTION Heretofore, various dyes have been labeled with iodineradioisotopes for combined imaging of the liver and biliary tract. Animaging agentsuch as iodine-131 labeled rose bengal' has proven useful;however, the relatively high radiation dose associated with it haslimited the extent of its use. The Journal of Nuclear Medicine, August,1972, Vol. 13 No. 8, atpages 652-4, suggests use of technetium-99mlabeled D-penicillamine as a cholescintigraphic agent prepared *in acidsolution, heatedand then neutralized before use. The Journal ofNucIearMedicinegtlune I973, Vol. 14 No. 6 at pages 41 1-12, suggests severaltechnetium-mercaptide derivatives as liverspecific imaging agents; Thesetechnetium labeled agents would result in diminished absorbed radiationdoses.

SPECIFICATION This invention relates generally to such hepato-biliaryimaging radiopharmaceuticals and more particularly to a new liverspecific radiopharmaceutical useful for studying liver, gall bladder andbiliary tract morphology and function.

The pharmaceutical consists of an aqueous solution of2-mercaptoisobutyric acid chelating reduced 99mtechnetium. A preferredform utilizes stannous tin as a reducing agent for the technetium-99m.In this form the imaging agent is simply and rapidly prepared by mixinga reagent containing the Z-mercaptoisobutyric acid and stannous tin withoxidant-free technetium- 99m pertechnetate which is readily available inphysiological saline solution.

In vivo distribution studies of the labeled material in experimentalanimals after intravenous injection show initial rapid clearance of theradioactivity from the blood plasma specifically by the liver withsubsequent, almost complete, excretion into the biliary tract.

The principal object of this invention is to produce a technetium-99mradiopharmaceutical which rapidly accumulates in the liver and then isexcreted from the liver to the biliary tract so as to be useful forhepaticbiliary morphology and function studies.

Another object of this invention is to produce such aradiopharmaceutical in a simple and rapid labeling procedure which doesnot involve heating or complicated pH adjustment.

Other objects and advantages of the new pharmaceutical and method willbecome apparent upon consideration of the following description of aspecific example.

The radiopharmaceutical has been prepared from a reagent made by mixingqual parts by volume of an aqueous solution of 3mM 2-mercaptoisobutyricacid and 1mm stannous chloride. To one part by volume of reagent isadded one part of oxidant-free 99m-technetium pertechnetate inphysiological saline solution. The combined solutions are mixedthoroughly by shaking. The technetium labeling is rapid. The binding of99m-technetium is essentially complete immediately after mixing and theagent is immediately ready for intravenous administration. Theradiopharmaceutical should be used within two hours after preparation.

Other proportions of Z-mercaptoisobutyric acid and stannous chloridecanbe used. No significant difference in in vivo distribution has beennoted if the labeled pha rmaceutical i'sprepared from reagent made with1 mM stannous chloride mixed with an equal volume of 3, 5, 7.5 orl mK/lconcentrations of 2-mercaptoisobutyric acid. Similarly, no significantdifference in the in vivo distribution was observed for theradiopharmaceutical wherein the reagent was prepared with equzivolumesof 1 mm stannous chloride and various 3 mM solutions of2-mercaptoisobutyric acid adjuste d in pH through the range of 2.9 to 7.The pH of 3 mM Lmercaptoisobutyric acid is about 2.9 and the pH range ofthe reagent of the specific example above is 2.5 to 3.5. Varyingconcentrations of stannous chloride or varying proportions of reagent totechnetium-99m pertechnetate also do not significantly affect in vivodistribution.

Following intravenous administration of the pharmaceutical inexperimental animals, the activity distributes inthe blood plasma fromwhich it is cleared by the liver exponentially, with a half-time of lessthan two minutes. The initial clearance rate is comparable to thatobtained with intravenously administered radiocolloids in the sameanimal species and extraction efficiency of the liver is almost 100%.The slope of the disappearance curve for radioactivity in the bloodplasma diminishes after five minutes, becoming fairly flat at 30 minuteswith approximately five percent of the administered dose remaining inthe blood plasma at that time. There is negligible uptake in the kidneysand spleen.

For example, in experimental rats, as early as five minutes afteradministration over of the remaining activity was in the liver and 6% inthe gut. The liver activity progressively cleared through the biliarytract to the gut. Three hours after administration, approximately 4% ofthe remaining activity was in the liver and 91% was found in the gut.Activity in the kidneys and spleen of animals sacrificed one hour afteradministration was negligible. Approximately 93% of the administeredactivity was found to have been excreted from the body within 24 hoursafter its administration.

The radiopharmaceutical is particularly useful for liver-biliary tractfunction studies. In scintiphotographs taken of experimental dogsfollowing intravenous ad ministration using a standard pinholecollimator fitted to a Nuclear Chicago H-P scintillation camera, theliver was clearly visualized seven minutes after administrationcomparable to that obtained using 99m-technetium labeled colloids,except that there was no activity seen in the spleen. At thirty minutes,the gall bladder was visualized and at 60 minutes after administrationthe gall bladder activity was predominant. Scintiphotographs taken to120 minutes after administration showed with good resolution theactivity in the common bile duct and in the region of the ampula.

The foregoing example and distribution data are illustrative of theimproved pharmaceutical and the simple method for instantly making it.Reducing agents for technetium-99m other than stannous tin may be usedto make the described pharmaceutical, i.e., ferrous, titanous, zirconyland chromous ions as well as Z-mercaptoisobutyric acid itself in highconcentration or low pH or elevated temperature as is known in the art.An hepato-biliary scintographic agent has been formed by (a) heatingtechnetium-99m pertechnetate in the presence of 2-mercaptoisobutyricacid (MIBA) for 15 minutes at 100C or (b) by contacting technetium-99mpertechnetate with high concentrations of Z-mercaptoisobutyric acid(MlBA), e.g. greater than millimolar, for several hours.

In view of the fact that various radiopharmaceuticals which do notaccumulate generally in normal tissue other than the target organ beingstudied, have been found to localize in infarcts and tumors, thedescribed radiopharmaceutical may have utility in radioisotope study oflocalized pathologic lesions. The scope of the invention is defined inthe appended claims.

We claim:

1. A radiopharmaceutical for scintigraphic organ imaging comprisingZ-mercaptoisobutyric acid labeled with reduced technetium-99m.

2. The radiopharmaceutical of claim 1 wherein the 2-mercaptoisobutyricacid is in aqueous solution and the technetium-99m is maintained in thereduced state by the presence of stannous tin.

3. A radiopharmaceutical consisting of mixed aqueous solutions ofZ-mercaptoisobutyric acid and stannous chloride; and technetium-99mpertechnetate in physiological saline.

4. The radiopharmaceutical of claim 3 wherein the molar proportion ofthe Z-mercaptoisobutyric acid to stannous chloride is 3 to l.

5. The method of making an instantly labeled liver specificradiopharmaceutical comprising the steps of preparing a reagent of mixedaqueous solutions of 2-n1ercaptoisobutyric acid and stannous chloride;

and

then adding to said reagent technetium-99m pertechnetate ions inphysiological saline solution.

6. The method of serially imaging the liver and biliary tract of apatient comprising the steps of preparing a radiopharmaceutical fromZ-mercaptoisobutyric acid and technetium-99m maintained in the reducedstate by the presence of stannous tin;

intravenously injecting the patient with said radiopharmaceutical; andthen scintigraphically imaging the liver and biliary tract to followmovement of radioactivity into the liver and then from it through thebiliary tract.

7. The method of imaging localized pathologic lesions in a patientcomprising the steps of preparing a radiopharmaceutical from2-mercaptoisobutyric acid labeled with reduced technetium- 99m;

intravenously injecting the patient with said radiopharmaceutical; and

then scintigraphically imaging the lesion.

1. A RADIOPHARMACEUTICAL FOR SCINTIGRAPHIC ORGAN IMAGING COMPRISING 2-MERCAPTOISOBUTYRIC ACID LABELED WITH REDUCED TECHNETIUM-99M.
 2. The radiopharmaceutical of claim 1 wherein the 2-mercaptoisobutyric acid is in aqueous solution and the technetium-99m is maintained in the reduced state by the presence of stannous tin.
 3. A radiopharmaceutical consisting of mixed aqueous solutions of 2-mercaptoisobutyric acid and stannous chloride; and technetium-99m pertechnetate in physiological saline.
 4. The radiopharmaceutical of claim 3 wherein the molar proportion of the 2-mercaptoisobutyric acid to stannous chloride is 3 to
 1. 5. The method of making an instantly labeled liver specific radiopharmaceutical comprising the steps of preparing a reagent of mixed aqueous solutions of 2-mercaptoisobutyric acid and stannous chloride; and then adding to said reagent technetium-99m pertechnetate ions in physiological saline solution.
 6. The method of serially imaging the liver and biliary tract of a patient comprising the steps of preparing a radiopharmaceutical from 2-mercaptoisobutyric acid and technetium-99m maintained in the reduced state by the presence of stannous tin; intravenously injecting the patient with said radiopharmaceutical; and then scintigraphically imaging the liver and biliary tract to follow movement of radioactivity into the liver and then from it through the biliary tract.
 7. The method of imaging localized pathologic lesions in a patient comprising the steps of preparing a radiopharmaceutical from 2-mercaptoisobutyric acid labeled with reduced technetium-99m; intravenously injecting the patient with said radiopharmaceutical; and then scintigraphically imaging the lesion. 